HIV-I, HIV-2 and SIV infect primate cells that express the CD4 receptor and a coreceptor that varies among different viral stains. Among the different target cells infected are three cell types that are important components of the immune system: immature dendritic cells, macrophages, and CD4+ T cells. The initial infection leads to a chronic, non-pathogenic, systemic infection in the naturally infected primates (Chimpanzees, Sooty Mangabeys and African green monkeys), but it progresses to the clinical manifestations of AIDS in humans and in Rhesus macaques infected in captivity. The molecular basis of the different outcomes in the different species is not understood. Because interactions with different host cell environments may contribute to the different outcomes, it is important to understand how primate and human immune cells respond to HIV/SIV. Recent studies have shown that the gene expression programs of dendritic cells and macrophages are modified by pathogen exposure and that these modifications can provide important clues to pathogenesis. We have shown that dendritic cell reprogramming by HIV can create conditions that favor virus spread, and that the effect is mediated by the HIV transactivator Tat. We propose to use newly developed experimental and computational technologies to investigate how the gene expression programs of specific cell types from different species are affected by HIV and SIV infection. To accomplish this, the specific aims of the proposal are 1) To monitor gene expression in dendritic cells, macrophages and T cells from both humans and chimpanzees after infection with HIV and after intracellular expression of Tat, and to identify genes that are differentially regulated in the two species. 2) To monitor gene expression in uninfected human and chimpanzee T cells after their exposure to the supernatant of donor-matched HIV-infected primary cells and to identify genes that are differentially regulated in the two species. The information obtained from these studies should allow us to discover how HIV perturbs host cell gene expression programs, may identify differences in perturbations that contribute to different disease outcomes, and may suggest new strategies for pathogen control.